A case of bidirectional conduction block within the superior vena cava induced by cryoballoon pulmonary vein isolation.

A 53-year-old male underwent a pulmonary vein isolation (PVI) of atrial fibrillation (AF) with a second-generation cryoballoon (CB). Although the patient maintained sinus rhythm after the PVI, a superior vena cava (SVC) fibrillation was recorded by a circular-multipolar-electrode catheter positioned inside the SVC that suggested conduction block between the right atrium (RA)-SVC connection. An adenosine triphosphate intravenous injection induced a dormant reconnection of the SVC myocardial sleeve and converted sinus rhythm to an AF rhythm. This case demonstrated that a CB application for the isolation of a right superior pulmonary vein could induce an electrical conduction block between the RA-SVC connection.

G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block.

Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies "sick sinus" syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca(2+) channels (Cav1.3(-/-)) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K(+) channel (IKACh) could rescue SSS and heart block in Cav1.3(-/-) mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3(-/-) mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3(-/-) mice or following selective inhibition of Cav1.3-mediated L-type Ca(2+) (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

Resolution of sinus bradycardia, high-grade heart block, and left ventricular systolic dysfunction with rituximab therapy in Henoch-Schonlein purpura.

Henoch-Schonlein purpura (HSP) is a rare, typically self-limited, multi-organ vasculitis. Cardiac involvement with HSP carries high morbidity and mortality, thus requiring early aggressive immunosuppressive therapy. We report a case of HSP complicated with acute systolic left ventricular (LV) dysfunction, symptomatic sinus bradycardia and high-grade atrio-ventricular (AV) heart block. Cyclophosphamide, a commonly used agent in HSP, was contraindicated due to the patient's presentation with acute renal failure. Treatment with monoclonal antibody rituximab and corticosteroids was initiated with an improvement in and resolution of LV systolic dysfunction, sinus bradycardia and AV block. We believe this is the first published report on rituximab treatment in HSP with cardiac involvement manifesting with severe LV systolic dysfunction, sinus bradycardia and high-grade AV block.

No histologic evidence of foetal cardiotoxicity following exposure to maternal hydroxychloroquine.

It is currently recommended that hydroxychloroquine (HCQ) be maintained during pregnancy in patients with systemic lupus erythematosus. Recent data suggest that this Toll-like receptor inhibitor may also reduce the recurrence rate of anti-SSA/Ro associated congenital heart block (CHB). This case report describes a unique situation in which a CHB-afflicted, HCQ-exposed pregnancy was electively terminated. The heart did not reveal any characteristic features of cardiotoxicity, providing further evidence supporting the safety of foetal exposure to HCQ.

Serial echocardiography for immune-mediated heart disease in the fetus: results of a risk-based prospective surveillance strategy.

OBJECTIVE: Mothers carrying anti-Ro antibodies are frequently referred for weekly echocardiograms to early detect and treat antibody-mediated fetal heart disease. We tested a surveillance strategy based on anti-Ro antibody titers. METHODS: From 2009 to 2014, 232 pregnancies were referred for maternal anti-Ro antibodies. At the baseline echocardiogram, anti-Ro titers were measured by enzyme-linked immunosorbent essay and results categorized as negative (<8 U/mL; n = 43; excluded), low-moderate positive (8-49 U/mL; n = 62; group 1) or high positive (50 - >100 U/mL; n = 127; group 2). Serial echocardiograms to ≥24 weeks were only recommended for group 2 mothers. RESULTS: Group 1 patients underwent significantly less fetal echocardiograms when compared with group 2 mothers (median 2 vs. 4; p < 0.001). Isolated endocardial fibroelastosis (n = 1) and incomplete (n = 4) or complete (n = 4) heart block were diagnosed in 9 (8%) pregnancies with anti-Ro titers >100 U/mL but none with lower titers (odds ratio 17.78; p = 0.004). Incomplete block and endocardial fibroelastosis regressed with transplacental corticosteroid and immune globulin therapy. CONCLUSIONS: Limiting serial fetal echocardiograms to women with high anti-Ro antibody levels is safe and more cost effective. While numbers of echocardiograms were significantly reduced in referrals with anti-Ro titers <50 U/mL, reversible abnormalities with prenatal treatment were detected by serial echocardiography in group 2 patients. © 2017 John Wiley & Sons, Ltd.

Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction.

The molecular pharmacology of the G protein-coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3-knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology.

Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system.

OBJECTIVES: Extension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit. METHODS: In this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1 week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation. RESULTS: In Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified. CONCLUSIONS: These data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.

Corticosteroid treatment normalizes QTc prolongation and improves heart block in an elderly patient with anti-Ro-positive systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystemic disease which potentially involves various organs including the skin, joints, kidneys, liver, hematopoetic system, and serous membranes. It is rarely seen in elderly males. The most common cardiovascular involvement type is pericarditis. Anti-Ro antibodies may be associated with neonatal lupus which causes heart blocks. Recent literature indicates that anti-Ro antibodies may be associated with various rhythm and conduction disturbances in the adulthood. The most common finding associated with anti-Ro antibodies is prolonged corrected QT (QTc) interval. Herein, we present an elderly male patient with anti-Ro-positive SLE associated with prolonged QTc interval and AV blocks that significantly improved after corticosteroid treatment.

Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents.

OBJECTIVE: The importance of maternal autoantibody levels in congenital heart block and elucidation of maternal factors that may reduce disease burden require further clarification. STUDY DESIGN: Pregnancies complicated by maternal anti-Ro antibodies from 2007 through 2011 were retrospectively reviewed. RESULTS: In all, 33 women were followed up throughout pregnancy. Semiquantitative maternal anti-La levels were significantly higher in pregnancies complicated by fetal heart block of any degree (median difference, 227.5; P = .04), but there was no difference in maternal anti-Ro levels. In all, 94% of fetuses maintained normal conduction when the mother was treated with hydroxychloroquine or daily prednisone therapy throughout pregnancy, compared to 59% in the untreated group (odds ratio, 0.1; P = .04). CONCLUSION: Pregnancies complicated by fetal heart block did not have higher levels of maternal anti-Ro antibodies. Maternal anti-La level may be a useful predictor of fetal heart block. Maternal treatment with either hydroxychloroquine or daily low-dose prednisone throughout pregnancy may provide a protective effect.

Worsening Wenckebach after calcium gluconate injection: not uncommon but frequently missed diagnosis.

The objective of the study is to demonstrate a common etiology of hyperkalemia and illustrate a potential iatrogenic errors in treatment.

Reflex syncope manifesting as orthostatic complete heart block.

A 52 year old patient presented with orthostatic dizziness and syncope caused by postural heart block. When the patient was supine, atrioventricular conduction was normal but when she assumed the upright posture she developed advanced atrioventricular block rapidly progressing to complete heart block. We are presenting a case of syncope caused by orthostatic heart block.

Rate-dependent and site-specific conduction block at the posterior right atrium and drug effects evaluated using a noncontact mapping system in patients with typical atrial flutter.

INTRODUCTION: Conduction block in the posterior right atrium (RA) plays an important role in perpetuating atrial flutter (AFL). Although conduction blocks have functional properties, it is not clear how the block line changes with the pacing rate, pacing site, and administration of antiarrhythmic drugs. METHODS AND RESULTS: Forty patients with typical AFL were enrolled. Pacing (110, 170, 230 ppm) from the coronary sinus ostium (CSo) and low lateral RA was performed. After 1 mg/kg pilsicainide (pure sodium channel blockade) administration, the pacing protocol was repeated. Conduction block was assessed based on a color-coded isopotential map and 20 points of virtual unipolar electrograms in the posterior RA using noncontact mapping. Block line proportion was defined as the percentage of length of the block line between the superior and inferior vena cava. The pacing rate-dependent extension of the block proportion was significant during pacing from both sides (pacing from the CSo: 59 ± 17% at 110 ppm, 69 ± 16% at 230 ppm, P < 0.05; pacing from the low lateral RA: 43 ± 19% at 110 ppm, 55 ± 22% at 230 ppm, P < 0.05). The block line was significantly longer during CSo pacing than during low lateral RA pacing at each rate (all P < 0.05). After pilsicainide administration, the block line extended further. CONCLUSION: In addition to pacing rate-dependent and site-dependent changes in the block line, pilsicainide further extended the block line length. This phenomenon explains the clinical observation that counterclockwise AFL occurs more frequently than clockwise AFL, and the mechanism of class IC AFL.

Association of the idiotype:antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune-associated congenital heart block.

OBJECTIVE: Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ∼18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype:antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB. METHODS: We studied 16 anti-Ro/SSA and anti-La/SSB-positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349-364aa of La/SSB (idiotype) and its antiidiotypic antibodies. RESULTS: Following IVIG treatment, serum titers of anti-La(349-364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349-364) was observed. The Id:anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P<0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349-364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied. CONCLUSION: This is the first study in humans to demonstrate that IVIG influences the Id-anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. OBJECTIVE: To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. METHODS: A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. RESULTS: The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). CONCLUSIONS: Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

Relapsing polychondritis associated with heart block.

OBJECTIVE: The present article aims at describing a rare case of an RP patient who evolved with heart block and was successfully treated with corticoid pulse therapy, without the need for pacemaker insertion. PATIENTS AND METHODS: A systematic research on relapsing polychondritis (RP) and heart block (HB) published in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo from 1966 to August 2020 was performed. RESULTS: It was found 10 studies on RP associated with HB, and we added a case. Most were male (7/10) with ages 30 to 66 years old. RP disease duration was 1 week-6 years. In most cases (7/10), the RP was active when the HB occurred. A complete HB was observed in 4/7, followed by type II degree block in 3/7, and one patient had a sinus node dysfunction. Most patients received glucocorticoids. A pacemaker was inserted in 4/9 cases. Good outcome was observed in 3/9 patients and mortality in 2/10. CONCLUSIONS: We report the first case of an RP patient who had a heart block and was successfully treated with methylprednisolone pulse therapy. The authors suggest that in these RP cases, an attempt with a glucocorticoid pulse therapy may be offered to treat the heart block and prevent the insertion of a pacemaker.

A case study of a pregnant patient with a congenital heart block accompanied by left isomerism and uncontrolled type 2 diabetes who was treated successfully with ritodrine.

We present a case study of a patient with a congenital heart block associated with a left isomerism that was diagnosed during the 26th week of gestation. The mother had type 2 diabetes mellitus that was difficult to control during the early stages of the pregnancy. A fetal echocardiogram revealed an atrioventricular dissociation, with an atrial rate of 120 bpm and a ventricular rate of 55 bpm. Subsequent examinations also revealed a left isomerism in the fetus. To increase the fetal heart rate, a continuous intravenous infusion of ritodrine was administered. The fetal ventricular rate rapidly increased to 65 bpm. The pregnancy successfully continued until term and a female infant weighing 3,182 g was born via a cesarean section. A subsequent surgery was performed to provide the infant with a permanent cardiac pacemaker, and notably, the child is now 4 months of age and her growth has been within the normal range.

Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.

BACKGROUND: Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES: Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS: This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS: By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS: These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

Prevention of complete heart block in children of mothers with anti-SSA/Ro and anti-SSB/La autoantibodies: detection and treatment of first-degree atrioventricular block.

PURPOSE OF REVIEW: To describe the results of two recent prospective studies that may indicate how to monitor, diagnose, and treat fetuses with neonatal lupus manifesting with heart involvement and to summarize additional research reports regarding the pathophysiology and outcomes of this rare condition. RECENT FINDINGS: The PR Interval and Dexamethasone Evaluation study found 10 cases of neonatal lupus (10%) with three first-degree atrioventricular blocks (AVBs) and three complete heart blocks. The study included 98 pregnancies in 95 women with anti-SSA/Ro antibodies who completed weekly fetal Doppler echocardiogram-based evaluation. The authors concluded that they were unable to detect first-degree AVB before progression to complete heart block. A similar observational prospective study was performed in 70 fetuses of 56 mothers using tissue velocity fetal kinetocardiogram for measurement of PR prolongation. In this study, six fetuses (8.5%) showed first-degree AVB, and fast normalization of heart function was achieved through maternal treatment with fluorinated steroids. The authors concluded that fetal kinetocardiogram can detect first-degree AVB in the fetus exposed to maternal anti-SSA/Ro or anti-SSB/La antibodies or both and that fluorinated steroids given on detection were associated with normalized atrioventricular conduction in fetuses with first-degree AVB. SUMMARY: Echo Doppler seems a less reliable method for early detection of fetus first-degree AVB, and it is suggested that fetal kinetocardiogram or fetal electrocardiography are preferred. Although atrioventricular block reverses spontaneously in some fetuses, parents and treating physicians should consider immediate treatment with fluorinated steroids once a first-degree AVB is detected due to the high risk of rapid progression to complete blockage.

Delayed thrombolysis in a patient presenting after 12 hours of chest pain, cardiogenic shock and life-threatening arrhythmias.

This 63 years old man presented to the emergency room with chest pain of more than 12 hours duration. The initial electrocardiogram showed as ST segment elevation inferior and right ventricular infarction. He developed signs and symptoms consistent with cardiogenic shock, followed by life threatening ventricular fibrillation and cardiac arrest. After repeated cardio-respiratory resuscitations and successful cardiac defibrillation, thrombolytic therapy was administered followed by clinical and hemodynamic improvements. One-week later cardiac catheterization and coronary arteriography were performed. The study showed 93% obstructive lesion in the proximal right coronary artery, an angioplasty was performed and a stent was placed. After appropriate re-adjustment of medical therapy, the patient was discharged and followed in the outpatient clinic. Although the time frame to administer thrombolytic therapy was over the 12 hours window as suggested by the AHA guidelines1, the potential risks benefits in the casepresented justifed the used of fibrinolytic therapy. Considering the multiple complications that the patient presented, fibrinolytic therapy needs to be considered even after 12 hours of symptoms initiation, particularly when facilities for primary percutaneous coronary interventions are not readily available.